Tetrahydrocarboline antiviral agents

ABSTRACT

The invention encompasses a series of tetrahydrocarboline compounds of Formula I which inhibit HIV entry by attaching to the exterior viral envelop protein gp120 and interrupting the viral entry process, possibly by interfering with the cellular receptor CD4. This action makes the compounds useful for treating HIV infection and AIDS. The invention also encompasses pharmaceutical compositions and methods for treating those infected with HIV.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application Ser.No. 60/574,669 filed May 26, 2004.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus-1) infection remains a major medicalproblem, with an estimated 42 million people infected worldwide at theend of 2002. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2002, 5.0 million newinfections were reported, and 3.1 million people died from AIDS.Currently available drugs for the treatment of HIV include ninenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations(zidovudine or AZT (or Retrovir®), didanosine (or Videx®),stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (orDDC or Hivid®), abacavir succinate (or Ziagen®), Tenofovir disoproxilfumarate salt (or Viread®), Combivir® (contains −3TC plus AZT),Trizivir® (contains abacavir, lamivudine, and zidovudine); threenon-nucleoside reverse transcriptase inhibitors: nevirapine (orViramune®), delavirdine (or Rescriptor®) and efavirenz (or Sustiva®),and seven peptidomimetic protease inhibitors or approved formulations:saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, andKaletra® (lopinavir and Ritonavir). Each of these drugs can onlytransiently restrain viral replication if used alone. However, when usedin combination, these drugs have a profound effect on viremia anddisease progression. In fact, significant reductions in death ratesamong AIDS patients have been recently documented as a consequence ofthe widespread application of combination therapy. However, despitethese impressive results, 30 to 50% of patients ultimately failcombination drug therapies. Insufficient drug potency, non-compliance,restricted tissue penetration and drug-specific limitations withincertain cell types (e.g. most nucleoside analogs cannot bephosphorylated in resting cells) may account for the incompletesuppression of sensitive viruses. Furthermore, the high replication rateand rapid turnover of HIV-1 combined with the frequent incorporation ofmutations, leads to the appearance of drug-resistant variants andtreatment failures when sub-optimal drug concentrations are present.Therefore, novel anti-HIV agents exhibiting distinct resistancepatterns, and favorable pharmacokinetic as well as safety profiles areneeded to provide more treatment options.

Currently marketed HIV-1 drugs are dominated by either nucleosidereverse transcriptase inhibitors or peptidomimetic protease inhibitors.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recentlygained an increasingly important role in the therapy of HIV infections.At least 30 different classes of NNRTI have been described in theliterature and several NNRTIs have been evaluated in clinical trials.Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) andbis(heteroaryl) piperazine derivatives (delavirdine) have been approvedfor clinical use. However, the major drawback to the development andapplication of NNRTIs is the propensity for rapid emergence of drugresistant strains, both in tissue cell culture and in treatedindividuals, particularly those subject to monotherapy. As aconsequence, there is considerable interest in the identification ofNNRTIs less prone to the development of resistance.

The compounds of this invention inhibit HIV entry by attaching to theexterior viral envelop protein gp120 and interrupting the viral entryprocess, possibly by interfering with the cellular receptor CD4.Compounds in this class have been reported to have antiviral activityagainst a variety of laboratory and clinical strains of HIV-1 and areeffective in treating HIV infection (see Hanna et al., Abstract 141presented at the 11th Conference on Retroviruses and OpportunisticInfections, San Francisco, Calif., Feb. 8-11, 2004; Lin et al., Poster534 presented at the 11th Conference on Retroviruses and OpportunisticInfections, San Francisco, Calif., Feb. 8-11, 2004; Hanna et al., Poster535 presented at the 11th Conference on Retroviruses and OpportunisticInfections, San Francisco, Calif., Feb. 8-11, 2004).

N-(3-aryl-3-oxo)acetyl piperidines have been disclosed. See Blair etal., U.S. Pat. No. 6,469,006; Wang et al., U.S. Pat. No. 6,476,034; Wanget al., U.S. Pat. No. 6,632,819; Wallace et al., U.S. Pat. No. 6,573,262(continuation-in-part application of U.S. Ser. No. 09/888,686 filed Jun.25, 2001); Wang et al. U.S. patent application Ser. No. 10/214,982 filedAug. 7, 2002 (continuation-in-part application of U.S. Ser. No.10/038,306 filed Jan. 2, 2002); Wang et al. patent application WO03/092695, published Nov. 13, 2003; Wang et al. U.S. patent application20040063744, published Apr. 1, 2004. Nothing in these references teachesor suggests the novel compounds of this invention or their use toinhibit HIV infection.

DESCRIPTION OF THE INVENTION

The invention encompasses a series of tetrahydrocarboline compounds ofFormula I including their pharmaceutically acceptable salts andsolvates, their pharmaceutical compositions, and their antiviral uses.

One aspect of the invention are compounds of Formula I

wherein:

-   X is CH or N;-   Y is C or N;-   R¹ is hydrogen, halo, or C₁₋₆alkoxy, provided that when Y is N, R¹    is absent;-   R² is hydrogen or halo;-   R³ is hydrogen, halo, C₁₋₆alkoxy, or CONHR⁶, or is a heteroaryl    moiety selected from the group consisting of pyrrolyl, imidazolyl,    triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and tetrazolyl, and    where the heteroaryl moiety is substituted with 0-2 C₁₋₆alkyl    groups;-   R⁴ is hydrogen, C₁₋₆alkyl, or phenyl;-   R⁵ is hydrogen, halo, trifluoromethyl, trifluoromethoxy, C₁₋₆alkyl,    or C₁₋₆alkoxy; and-   R⁶ is hydrogen or C₁₋₆alkyl;    or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention are compounds where X is N.

Another aspect of the invention are compounds of Formula I where X is Nand Y is C.

Another aspect of the invention are compounds of Formula I where R¹ ismethoxy.

Another aspect of the invention are compounds of Formula I where R² ishydrogen, fluorine, or chlorine.

Another aspect of the invention are compounds of Formula I where whereinR³ is methoxy or triazolyl where the triazolyl moiety is substitutedwith 0-1 C₁₋₆alkyl.

Another aspect of the invention are compounds of Formula I where R⁴ isphenyl.

Another aspect of the invention are compounds of Formula I where R⁵ isfluoro or trifluoromethyl.

Some compounds of the invention are2,3,4,5-tetrahydro-2-[2-(1H-indol-3-yl)-1,2-dioxoethyl]-1H-pyrido[4,3-b]indole;

2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(5-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole;

2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-2,3,4,5-tetrahydro-5-phenyl-1H-pyrido[4,3-b]indole;

2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-8-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indole;

2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-2,3,4,5-tetrahydro-8-(trifluoromethyl)-1H-pyrido[4,3-b]indole;

2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole;

8-fluoro-2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole;and

8-fluoro-2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole.

“Alkyl,” “alkoxy” and related terms with an alkyl moiety includestraight and branched configurations. “Aryl” includes carbocyclic andheterocyclic aromatic ring systems.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, lysine, arginine, N-methylglucamine, and zinc.

The invention also includes all solvated forms of the compounds,particularly hydrates. Solvates do not contribute significantly to thephysiological activity or toxicity of the compounds and as such functionas pharmacological equivalents. Solvates may form in stoichiometricamounts or may form from adventitious solvent or a combination of both.One type of solvate is hydrate, and some hydrated forms includemonohydrate, hemihydrate, and dihydrate.

Synthetic Methods

The compounds of this invention can be made according to the schemesprovided and other reactions known in the art. Schemes 1-3 illustrateprocedures for making and modifying some tetrahydrocarbolines. Othertetrahydrocarboline syntheses are known in the art. Scheme 4 illustratesa procedure for attaching a tetrahydrocarboline to a substituted aceticacid.

4-Azaindole and 4,6-diazaindole intermediates can be made according tomethods described in U.S. Pat. Nos. 6,476,034; 6,632,819; U.S. patentapplication Ser. No. 10/621,139, filed Jul. 16, 2003; U.S. patentapplication Ser. No. 10/214,982, filed Aug. 7, 2002; U.S. patentapplication Ser. No. 10/630,278, filed Jul. 30, 2003; and U.S. patentapplication Ser. No. 60/525,624, filed Nov. 26, 2003.

Cyanomethyl analogs of intermediates 4, 6, and 7 can be made by removingthe protecting group and treating the resulting amine withchloroacetonitrile and triethylamine. The cyanomethyl intermediates canbe coupled with a variety of indole-3-carboxylic methyl esters togenerate additional compounds of Formula I.

Biological Methods

Cells: (virus production) human embryonic kidney cell line, 293, waspropagated in Dulbecco's Modified Eagle Medium (Invitrogen, Carlsbad,Calif.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.);(virus infection) human epithelial cell line, HeLa, expressing the HIV-1receptor CD4 was propagated in Dulbecco's Modified Eagle Medium(Invitrogen, Carlsbad, Calif.) containing 10% fetal Bovine serum (FBS,Sigma, St. Louis, Mo.) and supplemented with 0.2 mg/mL Geneticin(Invitrogen, Carlsbad, Calif.).

Virus: single-round infectious reporter virus was produced byco-transfecting human embryonic kidney 293 cells with an HIV-1 envelopeDNA expression vector and a proviral cDNA containing an envelopedeletion mutation and the luciferase reporter gene inserted in place ofHIV-1 nef sequences. Transfections were performed using lipofectAMINEPLUS reagent as described by the manufacturer (Invitrogen, Carlsbad,Calif.).

Experiment: HeLa CD4 cells were plated in 96 well plates at a celldensity of 1×104 cells per well in 100 μl Dulbecco's Modified EagleMedium containing 10% fetal Bovine serum and incubated overnight.Compound was added in a 2 μl dimethylsulfoxide solution, so that thefinal assay concentration would be ≦10 μM. Single-round infectiousreporter virus (100 μL) in Dulbecco's Modified Eagle Medium was thenadded to the plated cells and compound at an approximate multiplicity ofinfection (MOI) of 0.01, resulting in a final volume of 200 μl per well.Virally-infected cells were incubated at 37 degrees Celsius, in a CO2incubator, and harvested 72 h after infection. Viral infection wasmonitored by measuring luciferase expression from viral DNA in theinfected cells using a luciferase reporter gene assay kit, as describedby the manufacturer (Roche Molecular Biochemicals, Indianapolis, Ind.).Infected cell supernatants were removed and 50 μl of lysis buffer wasadded per well. After 15 minutes, 50 μl of freshly-reconstitutedluciferase assay reagent was added per well. Luciferase activity wasthen quantified by measuring luminescence using a Wallac microbetaluminescence reader.

The percent inhibition for each compound was calculated by quantifyingthe level of luciferase expression in cells infected in the presence ofeach compound as a percentage of that observed for cells infected in theabsence of compound and subtracting such a determined value from 100.The effective concentration for fifty percent inhibition (EC₅₀) wascalculated with Microsoft Excel Xlfit curve fitting software. For eachcompound, curves were generated from percent inhibition calculated at 10different concentrations by using a four paramenter logistic model(model 205). The EC₅₀ data for the compounds is shown in Table 1. Table1.

TABLE 1 Example EC₅₀ 1 A 2 C 3 C 4 A 5 B 6 A 7 A 8 A 9 A EC₅₀ < 1 μM =A; 1-5 μM = B; >5 μM = C; >0.5 μM = D.

Pharmaceutical Composition and Methods of Use

The compounds of this invention inhibit HIV entry by attaching to theexterior viral envelop protein gp120 and interrupting viral entry,possibly by interfering with recognition of the cellular receptor CD4.Compounds in this class have been reported to have antiviral activityagainst a variety of laboratory and clinical strains of HIV-1 and areeffective in treating HIV infection (see Hanna et al., Abstract 141presented at the 11th Conference on Retroviruses and OpportunisticInfections, San Francisco, Calif., Feb. 8-11, 2004; Lin et al., Poster534 presented at the 11th Conference on Retroviruses and OpportunisticInfections, San Francisco, Calif., Feb. 8-11, 2004; Hanna et al., Poster535 presented at the 11th Conference on Retroviruses and OpportunisticInfections, San Francisco, Calif., Feb. 8-11, 2004).

Accordingly, another aspect of the invention is a method for treatingHIV infection in a human patient comprising administering atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, with apharmaceutically acceptable carrier.

Another aspect of the invention is a method for treating HIV infectionin a human patient comprising administering a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptable saltor solvate thereof, with a therapeutically effective amount of at leastone other agent used for treatment of AIDS or HIV infection. Somesuitable agents are nucleoside HIV reverse transcriptase inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, HIV proteaseinhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, andHIV integrase inhibitors.

Another aspect of the invention is a composition for treating HIVinfection in a human patient comprising administering a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof, with a pharmaceutically acceptablecarrier.

“Combination,” “coadministration,” “concurrent,” and similar termsreferring to the administration of compounds of Formula I with at leastone anti-HIV agent mean that the components are part of a combinationantiretroviral therapy or highly active antiretroviral therapy (HAART)as understood by practitioners in the field of AIDS and HIV infection.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of AIDS and HIV infection. In general, the goals of treatmentare suppression of viral load, restoration and preservation ofimmunologic function, improved quality of life, and reduction ofHIV-related morbidity and mortality.

“Patient” means a person infected with the HIV virus and suitable fortherapy as understood by practitioners in the field of AIDS and HIVinfection.

“Treatment,” “therapy,” “regimen” “HIV infection,” “AIDS” and relatedterms are used as understood by practitioners in the field of AIDS andHIV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of Formula I or its pharmaceutically acceptable salt and apharmaceutically acceptable carrier and may contain conventionalexcipients. A therapeutically effective amount is that which is neededto provide a meaningful patient benefit. Pharmaceutically acceptablecarriers are those conventionally known carriers having acceptablesafety profiles. Compositions encompass all common solid and liquidforms including capsules, tablets, losenges, and powders as well asliquid suspensions, syrups, elixers, and solutions. Compositions aremade using common formulation techniques, and conventional excipients(such as binding and wetting agents) and vehicles (such as water andalcohols) are generally used for compositions.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agentswill be present in a unit range similar to agents of that class usedclinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other antiretroviral agents will be present in a unitrange similar to agents of that class used clinically. Typically, thisis 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other antiretroviral agents used clinically. Typically,the daily dose will be 1-100 mg/kg body weight daily. Generally, morecompound is required orally and less parenterally. The specific dosingregime, however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating AIDS and HIVinfection. Some of these agents include HIV attachment inhibitors, CCR5inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integraseinhibitors, HIV nucleoside reverse transcriptase inhibitors, HIVnon-nucleoside reverse transcriptase inhibitors, HIV proteaseinhibitors, budding and maturation inhibitors, immunomodulators, andanti-infectives. In these combination methods, Compound 1 will generallybe given in a daily dose of 1-100 mg/kg body weight daily in conjunctionwith other agents. The other agents generally will be given in theamounts used therapeutically. The specific dosing regime, however, willbe determined by a physician using sound medical judgement.

Table 2 lists some agents useful in treating AIDS and HIV infectionwhich are suitable for this invention.

TABLE 2 DRUG NAME MANUFACTURER INDICATION ANTIVIRALS 097 Hoechst/BayerHIV infection, AIDS, (non-nucleoside ARC reverse transcriptaseinhibitor) Amprenavir Glaxo Wellcome HIV infection, AIDS, 141 W94 ARC GW141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIVinfection, AIDS, GW 1592 ARC (RT inhibitor) Acemannan Carrington LabsARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC,in combination with AZT AD-439 Tanox Biosystems HIV infection, AIDS, ARCAD-519 Tanox Biosystems HIV infection, AIDS, ARC Adefovir dipivoxilGilead Sciences HIV infection, ARC, AL-721 Ethigen PGL HIV positive,AIDS (Los Angeles, CA) Alpha Interferon Glaxo Wellcome Kaposi's sarcomaHIV in combination w/Retrovir Ansamycin Adria Laboratories ARC LM 427(Dublin, OH) Erbamont (Stamford, CT) Antibody which Advanced BiotherapyAIDS, ARC Neutralizes pH Concepts Labile alpha aberrant (Rockville, MD)Interferon AR177 Aronex Pharm HIV infection, AIDS, ARC Beta-fluoro-ddANat'l Cancer Institute AIDS-associated diseases BMS-232623 Bristol-MyersSquibb/ HIV infection, AIDS, (CGP-73547) Novartis ARC (proteaseinhibitor) BMS-234475 Bristol-Myers Squibb/ HIV infection, AIDS,(CGP-61755) Novartis ARC (protease inhibitor) CI-1012 Warner-LambertHIV-1 infection Cidofovir Gilead Science CMV retinitis, herpes,papillomavirus Curdlan sulfate AJI Pharma USA HIV infectionCytomegalovirus MedImmune CMV retinitis Immune globin Cytovene SyntexSight threatening Ganciclovir CMV peripheral, CMV retinitis DelaviridinePharmacia-Upjohn HIV infection, AIDS, (RT inhibitor) ARC Dextran SulfateUeno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka, positive asymptomaticJapan) ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddIBristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC;combinationwith AZT/d4T DMP-450 AVID HIV infection, AIDS, (proteaseinhibitor) (Camden, NJ) ARC Efavirenz DuPont Merck HIV infection, AIDS,(DMP 266) ARC (−)6-Chloro-4-(S)- cyclopropylethynyl- 4(S)-trifluoro-methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE (non-nucleosideRT inhibitor) EL10 Elan Corp, PLC HIV infection (Gainesville, GA)Famciclovir Smith Kline herpes zoster, herpes simplex FTC EmoryUniversity HIV infection, AIDS, (reverse transcriptase ARC inhibitor) GS840 Gilead HIV infection, AIDS, (reverse transcriptase ARC inhibitor)HBY097 Hoechst Marion HIV infection, AIDS, (non-nucleoside Roussel ARCreverse transcriptaseinhibitor) Hypericin VIMRx Pharm. HIV infection,AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's sarcoma,Interferon Beta (Almeda, CA) ARC Interferon alfa-n3 Interferon SciencesARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIVpositive, also in combination with AZT/ddI/ddC ISIS 2922 ISISPharmaceuticals CMV retinitis KNI-272 Nat'l Cancer InstituteHIV-associated diseases Lamivudine, 3TC Glaxo Wellcome HIV infection,AIDS, (reverse transcriptase ARC, also with AZT inhibitor) LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,AIDS, (protease inhibitor) Pharmaceuticals ARC Nevirapine BoeheringerHIV infection, AIDS, (RT inhibitor) Ingleheim ARC Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDSOctapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis,HIV Phosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, (protease inhibitor)ARC Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, AIDS, Tech (Houston, TX) ARC Ritonavir Abbott HIV infection,AIDS, (protease inhibitor) ARC Saquinavir Hoffmann- HIV infection, AIDS,(protease inhibitor) LaRoche ARC Stavudine; d4T Bristol-Myers Squibb HIVinfection, AIDS, Didehydrodeoxy- ARC thymidine Valaciclovir GlaxoWellcome Genital HSV & CMVinfections Virazole Viratek/ICN asymptomaticHIV- Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIVinfection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC,Kaposi's sarcoma, in combination with other therapies Tenofovirdisoproxil, Gilead HIV infection, AIDS fumarate salt (Viread ®) (reversetranscriptase inhibitor) Combivir ® GSK HIV infection, AIDS (reversetranscriptase inhibitor) abacavir succinate GSK HIV infection, AIDS (orZiagen ®) (reverse transcriptase inhibitor) Reyataz ® Bristol-MyersSquibb HIV infection, AIDS (atazanavir) Fuzeon Roche/Trimeris HIVinfection, AIDS, (Enfuvirtide, T-20) viral fusion inhibitor Trizivir ®HIV infection, AIDS Kaletra ® Abbott HIV infection, AIDS, ARCIMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia UpjohnAdvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246,738 American Cyanamid AIDS, Kaposi's sarcoma Lederle Labs EL10Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharmBlocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, incombination w/TNF (tumor necrosis factor) Granulocyte Genetics InstituteAIDS Macrophage Colony Sandoz Stimulating Factor GranulocyteHoechst-Roussel AIDS Macrophage Colony Immunex Stimulating FactorGranulocyte Schering-Plough AIDS, combination Macrophage Colony w/AZTStimulating Factor HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in CD4 Interleukin-2 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's sarcoma, (New Orleans, LA) ARC, PGL IMREG-2 Imreg AIDS,Kaposi's sarcoma, (New Orleans, LA) ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma AIDS,Muramyl-Tripeptide Amgen in combination w/AZT Granulocyte ColonyStimulating Factor Remune Immune Response Immunotherapeutic Corp. rCD4Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARChybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma, AIDS, Alfa 2a in combination w/AZTARC SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of oral Nystatin Pastille candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM& IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Human Ortho Pharm. Corp. Severe anemia assoc. Erythropoietinwith AZT therapy Recombinant Human Serono AIDS-related wasting, GrowthHormone cachexia Megestrol Acetate Bristol-Myers Squibb Treatment ofanorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

DESCRIPTION OF SPECIFIC EMBODIMENTS

LC/MS Method (compound identification). Column: Primesphere C-18 HC4.6×33 mm column; Standard LC Run Conditions (used unless otherwisenoted): Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100%Solvent B; Solvent A=10% MeCN-90% H₂O (5 mM NH4OAc), Solvent B=90%MeCN-10% H2O (5 mM NH4OAc); Gradient time: 2 minutes; Stop time: 3 min;Flow rate: 4 mL/min; Detector Wavelength: 220 nm.

Preparative HPLC Method (i.e., compound purification). Column: YMC PackC-18 20×100 mm column; Standard LC Run Conditions (used unless otherwisenoted): Gradient: 90% Solvent A/10% Solvent B to 0% Solvent A/100%Solvent B; Solvent A=10% MeCN-90% H2O (5 mM NH4OAc), Solvent B=90%MeCN-10% H2O (5 mM NH4OAc); Gradient time: 7 min; Stop time: 10 min;Flow rate: 20 mL/min; Detector Wavelength: 220 nm. Alternate solventsystem: Solvent A=10% MeCN-90% H2O-0.1% TFA; Solvent B=90% MeCN-10%H2O-0.1% TFA.

Compounds purified by preparative HPLC were diluted in MeOH or DMF (2mL) and purified using the following methods on a Shimadzu LC-10Aautomated preparative HPLC system or on a Shimadzu LC-8A automatedpreparative HPLC system with detector (SPD-10AV UV-VIS) wavelength andsolvent systems (A and B) the same as above.

Intermediate 1

Preparation of 1,3,4,5-Tetrahydropyrido[4,3-b]indole-2-carboxylic acidtert-butyl ester. General Method: A mixture of 2-iodoaniline (0.315 g,1.44 mmol), 4-oxo-1-piperidinecarboxylic acid tert-butyl ester (0.860 g,4.31 mmol), 1,4-diazabicyclo[2.2.2]octane (Dabco™) (0.483 mL, 4.31 mmol)and palladium acetate (0.016 g, 0.072 mmol) in dry DMF (7 mL) wasdegassed via vacuum/argon purging, and then it was heated to 110° C. for3.5 h. The reaction mixture was subsequently cooled to room temperatureand partitioned between ethyl acetate and water. The organic layer wasseparated, dried (MgSO₄), filtered and evaporated to dryness. Theresidue was chromatographed (SiO₂/hexanes:ethyl acetate, 1:1) to givethe title compound (0.068 g, 17%) as an off-white solid. ¹H NMR (400MHz, CDCl₃) δ 7.88 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz,1H), 7.12 (m, 2H), 4.64 (s, 2H), 3.82 (s, 2H), 2.82 (s, 2H), 1.50 (s,9H); LCMS: m/e 273 (M+H)⁺.

Intermediate 2

Preparation of8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylic acidtert-butyl ester. Prepared according to the general method to give thetitle compound (87% yield) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ7.90 (s, 1H), 7.20 (dd, J=8.8, 4.3 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.87(m, 1H), 4.58 (s, 2H), 3.81 (s, 2H), 2.81 (s, 2H), 1.50 (s, 9H); LCMS:m/e 291 (M+H)⁺.

Intermediate 3

Preparation of8-Trifluoromethyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylicacid tert-butyl ester. Prepared according to the general method to givethe title compound (17% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 8.62 (m, 1H), 7.70 (m, 1H), 7.36 (s, 2H), 4.66 (s, 2H), 3.83 (m, 2H),2.83 (t, J=5.8 Hz, 2H), 1.52 (s, 9H); LCMS: m/e 341 (M+H)⁺.

Intermediate 4

Preparation of5-Phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acidtert-butyl ester. A mixture of 1,1-diphenylhydrazine hydrochloride(0.365 g, 1.65 mmol) and 4-oxo-1-piperidinecarboxylic acid tert-butylester (0.329 g, 1.65 mmol) in pyridine (3 mL) was heated in a sealedtube at 120° C. with stirring for 3 h. The reaction mixture wassubsequently cooled to room temperature and partitioned between ethylacetate and water. The organic layer was separated, dried (MgSO₄),filtered and evaporated to dryness. The residue was chromatographed(SiO₂/hexanes:ethyl acetate, 3:2) to give the title compound (0.214 g,37%) as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (m, 2H), 7.40 (m,1H), 7.35 (m, 2H), 7.26 (m, 2H), 7.14 (m, 2H), 4.72 (s, 2H), 3.78 (s,2H), 2.71 (s, 2H), 1.51 (s, 9H); LCMS: m/e 349 (M+H)⁺.

Intermediate 6

Preparation of8-Fluoro-5-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid tert-butyl ester. To a suspension of NaH (80% in oil, 0.0190 g,0.633 mmol) in dry THF (1 mL), was added a solution of8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylic acidtert-butyl ester (0.114 g, 0.393 mmol) in THF (4 mL) via cannula. Thereaction mixture was allowed to stir at room temperature for 5 min andthen iodomethane (0.098 mL, 1.57 mmol) was added. The resulting mixturewas stirred for 2 h and then it was quenched with saturated aqueousammonium chloride and extracted with ethyl acetate. The organic phasewas separated, dried (MgSO₄), filtered and concentrated to dryness togive the title compound (0.109 g, 91%) as a yellow oil which was usedwithout further purification. LCMS: m/e 305 (M+H)⁺.

Intermediate 7

Preparation of8-Fluoro-5-phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid tert-butyl ester. A mixture of8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylic acidtert-butyl ester (0.455 g, 1.57 mmol), CuI (0.012 g, 0.065 mmol) andK₃PO₄ (0.579 g, 2.73 mmol) was suspended in toluene (5 mL) under Ar. Tothis mixture was added iodobenzene (0.145 mL, 1.30 mmol) andN,N′-dimethylethylenediamine (0.028 mL, 0.26 mmol) and then the reactionvessel was quickly sealed and the mixture was heated with stirring at150° C. (oil bath temperature) for 16 h. The cooled reaction mixture wassubsequently filtered (Celite) and the filtrate was concentrated todryness. The residue was purified by flash chromatography(SiO₂/hexanes-ethyl acetate, 80:20 to 20:80) to give the title compound(0.267 g, 46%) as a white foam. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (m, 2H),7.41 (m, 1H), 7.33 (m, 2H), 7.15 (m, 2H), 6.87 (m, 1H), 4.66 (s, 2H),3.77 (m, 2H), 2.70 (m, 2H), 1.51 (s, 9H); LCMS: m/e 367 (M+H)⁺.

EXAMPLE 1

1-(5-Phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione.General Method: A solution of5-phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acidtert-butyl ester (0.054 g, 0.155 mmol) in dry CH₂Cl₂ (2 mL) was treatedwith TFA (0.20 mL). After stirring the mixture for 1 h, the solvent wasevaporated in vacuo and the residue was dissolved in CHCl₃ (5 mL). Tothis mixture was added 4,7-dimethoxy-6-azaindol-3-yl-oxoacetic acid(0.042 g, 0.155 mmol), i-Pr2NEt (0.27 mL, 1.55 mmol) and then BOP-Cl(0.039 g, 0.153 mmol). The mixture was allowed to stir at roomtemperature for 2 h and then the solvent was removed in vacuo. Theresidue was partitioned with EtOAc-H2O, the organic phase was separatedand the aqueous phase was re-extracted with EtOAc (2×). The combinedorganic layers were washed (H2O, brine), dried (Na2SO4) and evaporated.The residue was purified by preparative HPLC to give the title compound(0.025 g, 33%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s,0.67H), 9.22 (s, 0.33H), 8.06 (d, J=3.0 Hz, 0.67H), 8.00 (d, J=3.0 Hz,0.33H), 7.59-7.07 (m, 10H), 4.11 (m, 1H), 4.05 (s, 3H), 3.88 (s, 1H),3.85 (m, 2H), 3.72 (s, 2H), 2.88 (m, 1H), 2.78 (m, 2H); LCMS: m/e 481(M+H)+.

EXAMPLE 2

1-(1,3,4,5-Tetrahydro-pyrido[4,3-b]indol-2-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione.Prepared according to the general method to give the title compound (53%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.23 (s, 0.67H), 9.14(s, 0.33H), 8.06 (d, J=3.0 Hz, 0.70H), 7.96 (d, J=3.0 Hz, 0.30H), 7.92(s, 0.40H), 7.89 (s, 0.60H), 7.52-6.99 (m, 5H), 4.15 (m, 1H), 4.05 (s,2H), 4.04 (s, 1H), 3.89 (m, 2H), 3.83 (s, 1H), 3.67 (s, 2H), 3.00 (m,1H), 2.89 (m, 2H); LCMS: m/e 405 (M+H)+.

EXAMPLE 3

1-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione.Prepared according to the general method to give the title compound (15%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 0.33H),11.06 (s, 0.67H), 8.17 (s, 0.56H), 8.09 (s, 0.44H), 7.42 (s, 0.38H),7.39 (s, 0.62H), 7.32-7.24 (m, 1H), 6.91-6.83 (m, 1H), 3.99 (m, 1H),3.97 (s, 2H), 3.96 (s, 1H), 3.74 (s, 1H), 3.70 (m, 2H), 3.59 (s, 2H),2.93 (m, 1H), 2.76 (m, 2H); LCMS: m/e 423 (M+H)+.

EXAMPLE 4

1-(8-Fluoro-5-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione.Prepared according to the general method to give the title compound (36%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s, 0.67H), 9.17(s, 0.33H), 8.04 (d, J=3.5 Hz, 0.69H), 7.96 (d, J=3.5 Hz, 0.31H), 7.42(s, 0.25H), 7.39 (s, 0.75H), 4.16 (m, 1H), 4.03 (s, 2H), 4.02 (s, 1H),3.90 (m, 2H), 3.84 (s, 1H), 3.69 (s, 2H), 3.65 (s, 1H), 3.62 (s, 2H),2.97 (m, 1H), 2.88 (m, 2H); LCMS: m/e 437 (M+H)+.

EXAMPLE 5

1-(8-Trifluoromethyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione.Prepared according to the general method to give the title compound (60%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 13.04 (m, 0.67H),12.96 (m, 0.33H), 11.50 (s, 0.33H), 11.46 (s, 0.67H), 8.18 (d, J=3.5 Hz,0.63H), 8.10 (d, J=3.5 Hz, 0.37H), 7.95 (s, 0.67H), 7.80 (s, 0.33H),7.51-7.31 (m, 3H), 4.01 (m, 1H), 3.98 (s, 2H), 3.97 (s, 1H), 3.74 (s,1H), 3.72 (m, 2H), 3.59 (s, 2H), 2.97 (m, 1H), 2.80 (m, 2H); LCMS: m/e473 (M+H)+.

EXAMPLE 6

1-(5-Phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-[4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl]-ethane-1,2-dione.Prepared according to the general method to give the title compound (56%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 11.01 (s, 0.7H),10.96 (s, 0.3H), 9.13 (s, 1H), 8.28 (d, J=3.0 Hz, 0.7H), 8.21 (d, J=3.5Hz, 0.3H), 7.73 (s, 0.3H), 7.70 (s, 0.7H), 7.59-7.04 (m, 9H), 4.13 (t,J=5.8 Hz, 1H), 3.98 (s, 1H), 3.89 (t, J=5.6 Hz, 2H), 3.84 (s, 2H), 2.90(m, 1H), 2.81 (m, 2H), 2.57 (s, 2H), 2.56 (s, 1H); LCMS: m/e 532 (M+H)+.

EXAMPLE 7

1-(5-Phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-[4-methoxy-7-(5-methyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl]-ethane-1,2-dione.Prepared according to the general method to give the title compound (41%yield) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.92 (s,0.67H), 10.87 (s, 0.33H), 8.27 (d, J=3.0 Hz, 1H), 8.17 (d, J=3.0 Hz,1H), 7.81 (s, 0.33H), 7.79 (s, 0.67H), 7.59-7.08 (m, 9H), 4.14 (m, 1H),3.90 (m, 2H), 3.87 (s, 3H), 3.08 (s, 3H), 2.90 (m, 1H), 2.82 (m, 2H);LCMS: m/e 532 (M+H)+.

EXAMPLE 8

1-(8-Fluoro-5-phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-[4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)-6-azaindol-3-yl]-ethane-1,2-dione.Prepared according to the general method to give the title compound (37%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) 11.03 (s, 0.64H), 11.00(s, 0.36H), 9.10 (s, 1H), 8.23 (d, J=3.5 Hz, 0.67H), 8.22 (d, J=3.0 Hz,0.33H), 7.74 (s, 0.29H), 7.71 (s, 0.71H), 7.57-6.84 (m, 9H), 4.13 (m,1H), 3.99 (s, 1H), 3.88 (m, 2H), 3.86 (s, 2H), 2.88 (m, 1H), 2.80 (m,2H), 2.56 (s, 2H), 2.55 (s, 1H); LCMS: m/e 550 (M+H)+.

EXAMPLE 9

1-(8-Fluoro-5-phenyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-[4-methoxy-7-(1,2,3-triazol-1-yl)-6-azaindol-3-yl]-ethane-1,2-dione.Prepared according to the general method to give the title compound (9%yield) as a white solid. ¹H NMR (400 MHz, CDCl3) 11.05 (s, 0.67H), 11.01(s, 0.33H), 8.76 (s, 1H), 8.35 (m, 0.72H), 8.29 (m, 0.28H), 7.94 (s,1H), 7.86 (s, 0.25H), 7.83 (s, 0.75H), 7.61-6.88 (m, 8H), 4.17 (s, 1H),4.07 (s, 1H), 3.94 (s, 2H), 3.92 (m, 2H), 2.92 (m, 1H), 2.85 (m, 2H);LCMS: m/e 536 (M+H)+.

1. A compound of Formula I

wherein: X is CH or N; Y is C or N; R¹ is hydrogen, halo, or C₁₋₆alkoxy,provided that when Y is N, R¹ is absent; R² is hydrogen or halo; R³ ishydrogen, halo, C₁₋₆alkoxy, or CONHR⁶, or is a heteroaryl moietyselected from the group consisting of pyrrolyl, imidazolyl, triazolyl,pyridinyl, pyrimidinyl, pyrazinyl, and tetrazolyl, and where theheteroaryl moiety is substituted with 0-2 C₁₋₆alkyl groups; R⁴ ishydrogen, C₁₋₆alkyl, or phenyl; R⁵ is hydrogen, halo, trifluoromethyl,trifluoromethoxy, C₁₋₆alkyl, or C₁₋₆alkoxy; and R⁶ is hydrogen orC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 2. A compoundof claim 1 where X is N.
 3. A compound of claim 1 where X is N and Y isC.
 4. A compound of claim 1 where R¹ is methoxy.
 5. A compound of claim1 where R² is hydrogen, fluorine, or chlorine.
 6. A compound of claim 1where R³ is methoxy or triazolyl where the triazolyl moiety issubstituted with 0-1 C₁₋₆alkyl.
 7. A compound of claim 1 where R⁴ isphenyl.
 8. A compound of claim 1 where R⁵ is fluoro or trifluoromethyl.9. A compound of claim 1 selected from the group consisting of2,3,4,5-tetrahydro-2-[2-(1H-indol-3-yl)-1,2-dioxoethyl]-1H-pyrido[4,3-b]indole;2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(5-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole;2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-2,3,4,5-tetrahydro-5-phenyl-1H-pyrido[4,3-b]indole;2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-8-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indole;2-[2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-1,2-dioxoethyl]-2,3,4,5-tetrahydro-8-(trifluoromethyl)-1H-pyrido[4,3-b]indole;2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole;8-fluoro-2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole;and8-fluoro-2,3,4,5-tetrahydro-2-[2-[4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-5-phenyl-1H-pyrido[4,3-b]indole;or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.